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Generation of Human Stem Cell-Derived Pancreatic Organoids (POs) for Regenerative Medicine

  • Victor Navarro-Tableros
  • Yonathan Gomez
  • Maria Felice Brizzi
  • Giovanni CamussiEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1212)

Abstract

Insulin-dependent diabetes mellitus or type 1 diabetes mellitus (T1DM) is an auto-immune condition characterized by the loss of pancreatic β-cells. The curative approach for highly selected patients is the pancreas or the pancreatic islet transplantation. Nevertheless, these options are limited by a growing shortage of donor organs and by the requirement of immunosuppression.

Xenotransplantation of porcine islets has been extensively investigated. Nevertheless, the strong xenoimmunity and the risk of transmission of porcine endogenous retroviruses, have limited their application in clinic. Generation of β-like cells from stem cells is one of the most promising strategies in regenerative medicine. Embryonic, and more recently, adult stem cells are currently the most promising cell sources exploited to generate functional β-cells in vitro. A number of studies demonstrated that stem cells could generate functional pancreatic organoids (POs), able to restore normoglycemia when implanted in different preclinical diabetic models. Nevertheless, a gradual loss of function and cell dead are commonly detected when POs are transplanted in immunocompetent animals. So far, the main issue to be solved is the post-transplanted islet loss, due to the host immune attack. To avoid this hurdle, nanotechnology has provided a number of polymers currently under investigation for islet micro and macro-encapsulation. These new approaches, besides conferring PO immune protection, are able to supply oxygen and nutrients and to preserve PO morphology and long-term viability.

Herein, we summarize the current knowledge on bioengineered POs and the stem cell differentiation platforms. We also discuss the in vitro strategies used to generate functional POs, and the protocols currently used to confer immune-protection against the host immune attack (micro- and macro-encapsulation). In addition, the most relevant ongoing clinical trials, and the most relevant hurdles met to move towards clinical application are revised.

Keywords

Cell differentiation Innovative therapies Pancreatic organoids Stem cells Type 1 diabetes mellitus 

Abbreviations

2D

Bi-dimensional

3D

Three-dimensional

A. ECM

Artificial ECM

AHFBRs

Alginate-filled hollow fiber bioreactors

ALDHhi

High aldehyde dehydrogenase activity

BAPs

Bioartificial pancreas

BCD

β-cell-derived cells

BM-MSC

Bone marrow MSC

CaO2

Calcium peroxide

Cas9

DNA endonuclease Cas9

CPO

Calcium peroxide

CRISPR

Clustered Regularly Interspaced Short Palindromic Repeats

Dex

Dexamethasone

ECM

Extracellular matrix

ED

Eudragit

EPCs

Endothelial progenitor cells

FBM

Functional β cell mass

FICCs

Fetal porcine islet-like cell clusters

FTY720

Fingolimod

GHRH

Growth hormone releasing hormone

Glut-2

Glucose transporter 2

HARV

High aspect ratio vessels

Hep-PEG

Glycosaminaglycans and heparin enriched capsules

hESCs

Human embryonic stem cells

hHPCs

Human hepatic progenitor cells

hiPSC

Human induced pluripotent stem cells

HLSC

Human liver stem cells

HLSC

Adult human liver stem-like cells

HMGB1

High mobility group box 1

huPI-MSC

Adult human pancreatic islet mesenchymal stromal cells

IBMIR

Instant blood-mediated inflammatory reaction

IL-2

Interleukine-2

IPCs

Insulin producing cells

iPSCs

Inducible pluripotent cells

KCl

Potassium chloride

LbL

Layer-by-layer

MGC

Methacrylated glycol chitosan

MMP

Matrix metalloproteinase

MP

Microparticles

mPEG

Methoxy polyethylene glycol

MSC

Mesenchymal stem cells

NeuroD1

Neuronal Differentiation 1 protein

NICC

Neonatal islet-like cell clusters

NICHE

Neovascularized implantable cell homing and encapsulation

NK

Natural Killer T cells

NPCCs

Neonatal pancreatic cell-clusters

NOD

Non-obese diabetic

PANC-1

Human pancreatic ductal-cells

PB

Probucol

PB-CDCA

PB-TCA alginate-microencapsulation

PCL/PVA

polyvinyl alcohol/polyvinyl alcohol

PDMS

Polydimethylsiloxane

PDX1

Pancreatic and duodenal homeobox 1

PEG

Poly(ethylene glycol)

PEGCol

Poly(ethylene glycol) hydrogels containing collagen type I

PEG-VS

Vinyl sulfone-terminated polyethylene glycol

PEOT/PBT

Poly(ethylene oxide terephthalate)-poly(butylene terephthalate)

PERV

Porcine retrovirus

PES/PVP

Polyethersulfone/polyvinylpyrrolidone

PFTBA

Perfluorotributylamine

PGA

Polyglycolides

PLA

Polylactic acid

PLGA

Poly(lactide-co-glycolide)

PLLA/PVA

Poly-L-lactic acid-polyvinyl alcohol

PLO

Poly-L-ornithine

PMAA-Na

Sodium polymethacrylate

POs

Pancreatic organoids

PSCs

Pancreatic stem cells

Ptf1a

Pancreas Associated Transcription Factor 1a

PTFE

Polytetra-fluoroethylene

PTX

Pentoxifylline

RWV

Rotating wall vessels

SF

Silk fibroin macroporous

SIPN

Semi-interpenetrating polymer network

SP

Saccharide-peptide

SPO

Sodium percarbonate

starPEG

Star-shaped polyethylene glycol

T1DM

Type 1 diabetes mellitus

T2DM

Type 2 diabetes mellitus

TCA

Taurocholic acid (bile acid)

Th

T-helper

TRAFFIC

Thread-reinforced alginate fiber for islets encapsulation

TNF-α

Tumor necrosis factor-alpha

VEGF

Vascular endothelial growth factor

VEGFR2

Vascular endothelial growth factor receptor 2

Notes

Author Contributions

V.N.T.: contributed to Manuscript writing and Figure preparation; Y.G.: contributed to manuscript writing and Figure preparation; M.F.B.: contributed to Manuscript editing; G.C.: contributed to Manuscript writing and editing.

Conflicts of Interest

The Authors declare no conflict of interest. GC is a component of the Scientific Advisory Board of UNISYTE.

Funding

This work has been supported by grants obtained by G.C. and M.F.B. from Unicyte AG.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Victor Navarro-Tableros
    • 1
  • Yonathan Gomez
    • 2
  • Maria Felice Brizzi
    • 2
  • Giovanni Camussi
    • 2
    • 3
    Email author
  1. 1.2i3T Società per la gestione dell’incubatore di imprese e per il trasferimento tecnologico ScarlUniversity of TurinTurinItaly
  2. 2.Department of Medical SciencesUniversity of TurinTurinItaly
  3. 3.Fondazione per la Ricerca Biomedica-ONLUSTurinItaly

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